EP1355636B1 - Transdermales therapeutisches system für die verabreichung carboxylgruppenhaltiger, nichtsteroidaler antiphlogistika, sowie verfahren zu seiner herstellung - Google Patents
Transdermales therapeutisches system für die verabreichung carboxylgruppenhaltiger, nichtsteroidaler antiphlogistika, sowie verfahren zu seiner herstellung Download PDFInfo
- Publication number
- EP1355636B1 EP1355636B1 EP02715442A EP02715442A EP1355636B1 EP 1355636 B1 EP1355636 B1 EP 1355636B1 EP 02715442 A EP02715442 A EP 02715442A EP 02715442 A EP02715442 A EP 02715442A EP 1355636 B1 EP1355636 B1 EP 1355636B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- active substance
- layer
- carboxyl group
- matrix
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 title claims abstract description 33
- 230000001225 therapeutic effect Effects 0.000 title claims abstract description 6
- 230000003637 steroidlike Effects 0.000 title claims abstract 5
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 title 1
- 239000010410 layer Substances 0.000 claims abstract description 52
- 239000011159 matrix material Substances 0.000 claims abstract description 50
- 239000013543 active substance Substances 0.000 claims abstract description 22
- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims abstract description 21
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims abstract description 16
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims abstract description 16
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000005642 Oleic acid Substances 0.000 claims abstract description 16
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims abstract description 16
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims abstract description 16
- 229910001414 potassium ion Inorganic materials 0.000 claims abstract description 10
- 229920000058 polyacrylate Polymers 0.000 claims abstract description 9
- 239000000470 constituent Substances 0.000 claims abstract description 7
- 239000011241 protective layer Substances 0.000 claims abstract description 6
- 229940123907 Disease modifying antirheumatic drug Drugs 0.000 claims abstract 4
- 230000003356 anti-rheumatic effect Effects 0.000 claims abstract 4
- 239000003435 antirheumatic agent Substances 0.000 claims abstract 4
- 229920000139 polyethylene terephthalate Polymers 0.000 claims description 14
- 239000005020 polyethylene terephthalate Substances 0.000 claims description 14
- -1 aluminium ions Chemical class 0.000 claims description 12
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 10
- 229960001680 ibuprofen Drugs 0.000 claims description 10
- 239000000853 adhesive Substances 0.000 claims description 9
- 230000001070 adhesive effect Effects 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 8
- 229910052782 aluminium Inorganic materials 0.000 claims description 5
- 239000004744 fabric Substances 0.000 claims description 5
- 229920006267 polyester film Polymers 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 claims description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 4
- 229960002390 flurbiprofen Drugs 0.000 claims description 4
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 claims description 4
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 4
- 229960000991 ketoprofen Drugs 0.000 claims description 4
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 claims description 3
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 3
- 239000011248 coating agent Substances 0.000 claims description 3
- 238000000576 coating method Methods 0.000 claims description 3
- 229960001419 fenoprofen Drugs 0.000 claims description 3
- 229960002009 naproxen Drugs 0.000 claims description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 3
- 229960001312 tiaprofenic acid Drugs 0.000 claims description 3
- GUHPRPJDBZHYCJ-UHFFFAOYSA-N tiaprofenic acid Chemical compound S1C(C(C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000005062 Polybutadiene Substances 0.000 claims description 2
- 229920002367 Polyisobutene Polymers 0.000 claims description 2
- 229960004892 acemetacin Drugs 0.000 claims description 2
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 claims description 2
- 229920001400 block copolymer Polymers 0.000 claims description 2
- 229960001259 diclofenac Drugs 0.000 claims description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 229960000905 indomethacin Drugs 0.000 claims description 2
- 229960003768 lonazolac Drugs 0.000 claims description 2
- XVUQHFRQHBLHQD-UHFFFAOYSA-N lonazolac Chemical compound OC(=O)CC1=CN(C=2C=CC=CC=2)N=C1C1=CC=C(Cl)C=C1 XVUQHFRQHBLHQD-UHFFFAOYSA-N 0.000 claims description 2
- 229920002857 polybutadiene Polymers 0.000 claims description 2
- 229920001195 polyisoprene Polymers 0.000 claims description 2
- 150000005599 propionic acid derivatives Chemical class 0.000 claims description 2
- 229960001017 tolmetin Drugs 0.000 claims description 2
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 claims description 2
- KILURZWTCGSYRE-LNTINUHCSA-K (z)-4-bis[[(z)-4-oxopent-2-en-2-yl]oxy]alumanyloxypent-3-en-2-one Chemical compound CC(=O)\C=C(\C)O[Al](O\C(C)=C/C(C)=O)O\C(C)=C/C(C)=O KILURZWTCGSYRE-LNTINUHCSA-K 0.000 claims 2
- 239000004411 aluminium Substances 0.000 claims 2
- 229920000728 polyester Polymers 0.000 claims 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 1
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 1
- 238000004080 punching Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 42
- 239000004480 active ingredient Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 235000014113 dietary fatty acids Nutrition 0.000 description 9
- 229930195729 fatty acid Natural products 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 239000000463 material Substances 0.000 description 7
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 150000004665 fatty acids Chemical class 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 5
- XBIUWALDKXACEA-UHFFFAOYSA-N 3-[bis(2,4-dioxopentan-3-yl)alumanyl]pentane-2,4-dione Chemical compound CC(=O)C(C(C)=O)[Al](C(C(C)=O)C(C)=O)C(C(C)=O)C(C)=O XBIUWALDKXACEA-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 3
- 238000004873 anchoring Methods 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000003513 alkali Substances 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- GOXQRTZXKQZDDN-UHFFFAOYSA-N 2-Ethylhexyl acrylate Chemical compound CCCCC(CC)COC(=O)C=C GOXQRTZXKQZDDN-UHFFFAOYSA-N 0.000 description 1
- 229920002799 BoPET Polymers 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 239000005639 Lauric acid Substances 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 101710164303 N-succinylamino acid racemase Proteins 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002313 adhesive film Substances 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 101710125387 o-succinylbenzoate synthase Proteins 0.000 description 1
- QWIDXEUVWSDDQX-SVMKZPJVSA-N octadecanoic acid;(z)-octadec-9-enoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O QWIDXEUVWSDDQX-SVMKZPJVSA-N 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- MLICVSDCCDDWMD-KVVVOXFISA-M potassium;(z)-octadec-9-enoate Chemical compound [K+].CCCCCCCC\C=C/CCCCCCCC([O-])=O MLICVSDCCDDWMD-KVVVOXFISA-M 0.000 description 1
- 238000010526 radical polymerization reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to transdermal therapeutic systems (TTS) intended for the administration of carboxyl group-containing, non-steroidal anti-inflammatory drugs.
- TTS transdermal therapeutic systems
- the invention relates to TTS of the type mentioned which have a matrix based on carboxyl-containing polyacrylate pressure-sensitive adhesives.
- the present invention also includes methods for the production of TTS of the type mentioned.
- Active ingredients from the group of carboxyl-containing nonsteroidal anti-inflammatory drugs or anti-inflammatory drugs are widely used in the treatment of inflammation, inflammatory joint diseases, rheumatic diseases and the consequent pain conditions.
- acetic acid derivatives such as indomethacin, acemetacin, tolmetin, diclofenac and Lonazolac, and on the other hand representatives of propionic acid derivatives (Profene), such.
- Ibuprofen, flurbiprofen, fenoprofen, ketoprofen, naproxen and tiaprofen Since by the oral intake of these active substances often side effects such.
- JP 4074119 A proposed the addition of an alkali metal hydroxide. However, the addition of a permeation-promoting fatty acid is not provided.
- the object of the present invention was therefore to provide transdermal therapeutic systems which are suitable for the administration of said active substances, and which are characterized by the in DE 198 30 649 A1 Describe advantageous properties described, but without having the disadvantages described above.
- the drug-containing matrix is prepared on the basis of a carboxyl-containing polyacrylate adhesive, and that it has a content of oleic acid and potassium ions, wherein the proportion of potassium ions in the range of 5 to 50%, based on the equivalent weight of the sum of all carboxyl-containing matrix constituents.
- the matrix layers according to the invention also have opposite DE 198 30 649 A1 a significantly improved cohesion of the pressure-sensitive adhesive matrix layer and a perfect anchoring on backing layers of PET materials. Across from JP 4074119 results in a significant improvement of the skin permeation of the drug due to the permeation-promoting effect of the oleic acid contained.
- carboxyl group-containing polyacrylate adhesive for the preparation of the active ingredient matrix of the invention preferably carboxyl-containing pressure-sensitive adhesives are used, which are sold under the name "Durotak” by the company. National Starch, in particular the pressure sensitive adhesive Durotak 387-2353.
- other polyacrylate adhesives which are prepared by radical polymerization of acrylic and / or methacrylic acid and their derivatives (for example 2-ethylhexyl acrylate) are also fundamentally suitable.
- such polymers may also contain other comonomers, e.g. B. Vinyl acetate.
- suitable mixtures of various carboxyl-containing polyacrylate adhesive can be used.
- the basis weight of the matrix layer is preferably in the range of 30-120 g / m 2 , wherein a basis weight in the range of 50-80 g / m 2 is particularly preferred.
- the potassium ions contained in the matrix layers according to the invention are preferably added as potassium hydroxide. Since the formulations according to the invention have at least three carboxyl-containing constituents, namely the active ingredient, oleic acid and the carboxyl-containing pressure-sensitive adhesive, it is very difficult to determine with which of these carboxyl-containing components salification takes place and in what proportion. Therefore, an experimental investigation of this salt formation was omitted.
- the amount of potassium hydroxide contained is a percentage of the equivalent weight of the sum of the carboxyl group-containing components of the matrix (see Example 9).
- An amount of 100% potassium hydroxide equivalents corresponds to the neutralization of all carboxyl group-containing matrix constituents. It has been observed that a significant increase in the cohesion of the matrix film occurs only when at least an amount of 5%, better 10% Kaliumhydroxidäquivalenten added.
- the amount of KOH added exceeds a value of 50% potassium hydroxide equivalents, the matrix layer or the matrix film greatly loses stickiness. At the same time, the hydrophilicity of the matrix increases sharply, so that the matrix film, when worn on the skin, starts to turn white due to absorption of skin moisture and loses its adhesive power.
- KOH is added in an amount of 10 to 40% potassium hydroxide equivalents, with optimum results being achieved at about 30% potassium hydroxide equivalents.
- the content of oleic acid may be between 5 and 25 wt .-%, based on the matrix layer; Preferably, oleic acid is added in an amount of 10-20% by weight.
- active substances from the group of carboxyl group-containing NSARs preferably ibuprofen, flurbiprofen, fenoprofen, ketoprofen, naproxen and tiaprofen are used, with ibuprofen being particularly preferred; but it can also be used other representatives of this group of drugs, such as the aforementioned active ingredients.
- the active ingredient is substantially present as (S) -enantiomer.
- the active ingredient concentration in the matrix is preferably 5 to 25 wt .-%, particularly preferably 10 to 20 wt .-%.
- the pressure-sensitive adhesive is crosslinked by aluminum ions.
- the crosslinking reagent used is preferably aluminum acetylacetonate.
- the crosslinking additionally improves the cohesion of the adhesive layer.
- Aluminum acetylacetonate is preferably added in a concentration of 0.01 to 0.2 wt .-%, with the concentration range of 0.05 to 0.1 wt .-% is particularly preferred. The stated percentages are calculated as the aluminum ion concentration in the active substance-containing adhesive matrix.
- the present invention also includes those embodiments in which between the active substance-containing matrix layer of the TTS and its backing layer, a water vapor barrier Intermediate layer is attached, which acts occlusive when worn on the skin (see Fig. 2 ).
- This intermediate layer is preferably constructed of hydrocarbon polymers, e.g. Example of polyisobutylene, polybutadiene, polyisoprene or block copolymers of styrene with butadiene or isoprene.
- the basis weight of the intermediate layer is in the range of 10 to 100 g / m 2 , preferably in the range of 20 to 80 m 2 .
- the attachment of such an intermediate layer is particularly advantageous if the backing layer consists of water vapor permeable material.
- the material used for the backing layer of the TTS according to the invention is preferably polyethylene terephthalate (PET) film, but particularly preferably longitudinal and transverse elastic, air and water vapor permeable PET fabric used.
- PET polyethylene terephthalate
- other polyester films or fabrics known to those skilled in the art may also be used, with materials having elastic properties being preferred.
- plastic films for example, by siliconization
- PET polyethylene terephthalate
- the structure of the TTS according to the invention is based on the Fig. 1 and 2 exemplified. These are schematic, simplified drawings, each showing a TTS in a sectional view.
- Fig. 1 shows a TTS, consisting of a backing layer (1) and a homogeneous, active ingredient-containing matrix layer (2).
- the skin-facing side of the matrix layer (2) is covered with a removable protective layer (3).
- Fig. 2 shows a further preferred structure of a TTS according to the invention, which also has a backing layer (1), a homogeneous active ingredient-containing matrix layer (2) and a removable protective layer (3).
- a water vapor barrier intermediate layer (4) between matrix layer (2) and back layer (1).
- Example 9 the oleic acid is first stirred into the Durotak pressure-sensitive adhesive solution (Durotak 387-2353, National Starch Co.). Thereafter, potassium hydroxide in the form of a 10% (wt .-%) solution in methanol is slowly added with stirring. Finally, ibuprofen is dissolved in this approach and the powdered crosslinking reagent aluminum acetylacetonate added and stirred until dissolved. To adjust a viscosity suitable for the coating, ethyl acetate is added to the final solution as needed.
- Durotak pressure-sensitive adhesive solution Durotak 387-2353, National Starch Co.
- This adhesive solution is coated on a siliconized polyester film (PET, 100 microns).
- PET siliconized polyester film
- the coating thickness is adjusted so that after drying for 10 minutes at 60 ° C in an exhaust air oven, a film with a basis weight of 60 to 80 g / m 2 is obtained.
- the dried adhesive film is provided with a longitudinally and transversely elastic PET fabric (KOB Karl Otto Braun) as backing layer. Subsequently, individual plasters of suitable shape and size are punched out of this laminate.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CY20081100839T CY1108250T1 (el) | 2001-01-30 | 2008-08-11 | Διαδερμικο θεραπευτικο συστημα για τη χορηγηση μη στεροειδικων αντιφλογιστικων που φερουν καρβοξυλομαδες, καθως και μεθοδος για την παραγωγη του |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10103860A DE10103860B4 (de) | 2001-01-30 | 2001-01-30 | Transdermales therapeutisches System für die Verabreichung carboxylgruppenhaltiger, nichtsteroidaler Antiphlogistika, sowie Verfahren zu seiner Herstellung |
DE10103860 | 2001-01-30 | ||
PCT/EP2002/000417 WO2002060418A1 (de) | 2001-01-30 | 2002-01-17 | Transdermales therapeutisches system für die verabreichung carboxylgruppenhaltiger, nichtsteroidaler antiphlogistika, sowie verfahren zu seiner herstellung |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1355636A1 EP1355636A1 (de) | 2003-10-29 |
EP1355636B1 true EP1355636B1 (de) | 2008-05-14 |
Family
ID=7672050
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02715442A Expired - Lifetime EP1355636B1 (de) | 2001-01-30 | 2002-01-17 | Transdermales therapeutisches system für die verabreichung carboxylgruppenhaltiger, nichtsteroidaler antiphlogistika, sowie verfahren zu seiner herstellung |
Country Status (11)
Country | Link |
---|---|
US (1) | US7332180B2 (ko) |
EP (1) | EP1355636B1 (ko) |
JP (1) | JP4160394B2 (ko) |
KR (1) | KR100822418B1 (ko) |
AT (1) | ATE395050T1 (ko) |
CY (1) | CY1108250T1 (ko) |
DE (2) | DE10103860B4 (ko) |
DK (1) | DK1355636T3 (ko) |
ES (1) | ES2307737T3 (ko) |
PT (1) | PT1355636E (ko) |
WO (1) | WO2002060418A1 (ko) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2946754B1 (de) | 2014-05-23 | 2017-03-01 | AMW GmbH | Pflaster mit bielastischer rückschicht |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE10102817B4 (de) * | 2001-01-23 | 2006-01-12 | Lts Lohmann Therapie-Systeme Ag | Vorrichtung und Verfahren zur Hitzepulsgestützten transdermalen Applikation von Wirkstoffen |
DE10159745A1 (de) * | 2001-12-05 | 2003-07-03 | Lohmann Therapie Syst Lts | Transdermales Therapeutisches System mit verbessertem Langzeittragekomfort |
US8133505B2 (en) | 2002-10-31 | 2012-03-13 | Transpharma Medical Ltd. | Transdermal delivery system for dried particulate or lyophilized medications |
IL152574A (en) * | 2002-10-31 | 2009-09-22 | Transpharma Medical Ltd | A system for passing through the skin of dry items or dried medicines |
US20050137262A1 (en) * | 2003-12-22 | 2005-06-23 | Hu Patrick C. | Highly concentrated pourable aqueous solutions of potassium ibuprofen, their preparation and their uses |
DE102004039728A1 (de) * | 2004-08-16 | 2006-02-23 | Beiersdorf Ag | Wirkstoffhaltiges Tape zur Behandlung von Gelenkerkrankungen |
KR100663163B1 (ko) | 2005-10-24 | 2007-01-02 | (주)아모레퍼시픽 | 비스테로이드성 소염진통제를 함유하는 경피 투여 제제 |
TWI389709B (zh) | 2005-12-01 | 2013-03-21 | Novartis Ag | 經皮治療系統 |
DE102006054733A1 (de) | 2006-11-21 | 2008-05-29 | Lts Lohmann Therapie-Systeme Ag | Transdermales therapeutisches Systems mit hoher Wirkstoffausnutzungsrate und Dosiergenauigkeit |
JP5209433B2 (ja) * | 2007-10-19 | 2013-06-12 | 日東電工株式会社 | 貼付製剤 |
JP5686132B2 (ja) * | 2010-04-13 | 2015-03-18 | 東亞合成株式会社 | 医療用粘着剤組成物、医療用貼付剤及び該組成物の製造方法 |
ES2545094T3 (es) * | 2010-12-14 | 2015-09-08 | Acino Ag | Sistema terapéutico transdérmico para la administración de un principio activo |
DE102011114411A1 (de) * | 2011-09-26 | 2013-03-28 | Lts Lohmann Therapie-Systeme Ag | Pflaster mit einstellbarer Okklusion |
WO2014159798A1 (en) | 2013-03-13 | 2014-10-02 | Avery Dennison Corporation | Improving adhesive properties |
JP2018537451A (ja) * | 2015-11-16 | 2018-12-20 | ノーヴェン ファーマシューティカルズ インコーポレイテッド | 経皮薬物送達システムのための伸縮可能なバッキング層 |
CN109862885A (zh) * | 2016-10-18 | 2019-06-07 | Lts勒曼治疗系统股份公司 | 双层局部治疗系统 |
WO2019068288A1 (de) | 2017-10-04 | 2019-04-11 | Berlimed International Research Gmbh | Wirkstoff und wirkstoffmatrix enthaltendes produkt zur transdermalen wirkstoffabgabe sowie dessen herstellung und verwendung sowie die wirkstoffmatrix, ihre herstellung und verwendung |
DE102021128911A1 (de) | 2021-11-05 | 2023-05-11 | Lts Lohmann Therapie-Systeme Ag. | Diclofenac enthaltendes tts mit dimethylpropylenharnstoff |
DE102021128912A1 (de) | 2021-11-05 | 2023-05-11 | Lts Lohmann Therapie-Systeme Ag. | Okklusives pflaster mit flexibler backing |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3046346B2 (ja) | 1990-03-12 | 2000-05-29 | 昭和電工株式会社 | 外用剤基剤又は補助剤とそれを含有する人又は動物の外用剤 |
DE4020144A1 (de) * | 1990-06-25 | 1992-01-09 | Lohmann Therapie Syst Lts | Pflaster mit hohem gehalt an weichmachenden inhaltsstoffen |
JPH0474113A (ja) * | 1990-07-13 | 1992-03-09 | Kao Corp | 染毛剤組成物 |
JP3046330B2 (ja) * | 1990-07-16 | 2000-05-29 | 日東電工株式会社 | 貼付製剤 |
US5125995A (en) * | 1990-09-10 | 1992-06-30 | Minnesota Mining And Manufacturing Company | Method of using a water-dispersible pressure sensitive adhesive tape on cloth body coverings |
US5906830A (en) * | 1995-09-08 | 1999-05-25 | Cygnus, Inc. | Supersaturated transdermal drug delivery systems, and methods for manufacturing the same |
DE19706824C1 (de) * | 1997-02-21 | 1998-03-26 | Lohmann Therapie Syst Lts | Transdermales oder topisches Plastersystem mit Polyacrylatmatrix mit verbesserten physikalischen Eigenschaften |
DE19814083C2 (de) * | 1998-03-30 | 2002-02-07 | Lohmann Therapie Syst Lts | Verfahren zur Herstellung von transdermalen therapeutischen Systemen unter Verwendung von basischen Alkalimetallsalzen zur Umwandlung von Wirkstoffsalzen in die freien Basen |
JP4275768B2 (ja) | 1998-06-18 | 2009-06-10 | 久光製薬株式会社 | 水性粘着膏体 |
DE19830649C2 (de) * | 1998-07-09 | 2003-04-10 | Lohmann Therapie Syst Lts | Topisches Pflaster mit nichtsteroidalen Antirheumatika mit Säuregruppe |
DE19918106A1 (de) * | 1999-04-22 | 2000-10-26 | Lohmann Therapie Syst Lts | Transdermales therapeutisches System mit neutralisierten Acrylathaftklebern |
-
2001
- 2001-01-30 DE DE10103860A patent/DE10103860B4/de not_active Expired - Fee Related
-
2002
- 2002-01-17 DK DK02715442T patent/DK1355636T3/da active
- 2002-01-17 DE DE50212267T patent/DE50212267D1/de not_active Expired - Lifetime
- 2002-01-17 ES ES02715442T patent/ES2307737T3/es not_active Expired - Lifetime
- 2002-01-17 KR KR1020037009972A patent/KR100822418B1/ko active IP Right Grant
- 2002-01-17 AT AT02715442T patent/ATE395050T1/de active
- 2002-01-17 US US10/470,701 patent/US7332180B2/en not_active Expired - Lifetime
- 2002-01-17 EP EP02715442A patent/EP1355636B1/de not_active Expired - Lifetime
- 2002-01-17 PT PT02715442T patent/PT1355636E/pt unknown
- 2002-01-17 WO PCT/EP2002/000417 patent/WO2002060418A1/de active IP Right Grant
- 2002-01-17 JP JP2002560611A patent/JP4160394B2/ja not_active Expired - Lifetime
-
2008
- 2008-08-11 CY CY20081100839T patent/CY1108250T1/el unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2946754B1 (de) | 2014-05-23 | 2017-03-01 | AMW GmbH | Pflaster mit bielastischer rückschicht |
Also Published As
Publication number | Publication date |
---|---|
KR20030072609A (ko) | 2003-09-15 |
DE50212267D1 (de) | 2008-06-26 |
US20040071764A1 (en) | 2004-04-15 |
JP4160394B2 (ja) | 2008-10-01 |
JP2004516916A (ja) | 2004-06-10 |
US7332180B2 (en) | 2008-02-19 |
DE10103860B4 (de) | 2004-12-23 |
KR100822418B1 (ko) | 2008-04-16 |
PT1355636E (pt) | 2008-08-25 |
WO2002060418A1 (de) | 2002-08-08 |
DE10103860A1 (de) | 2002-08-14 |
ATE395050T1 (de) | 2008-05-15 |
DK1355636T3 (da) | 2008-09-08 |
ES2307737T3 (es) | 2008-12-01 |
CY1108250T1 (el) | 2014-02-12 |
EP1355636A1 (de) | 2003-10-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1355636B1 (de) | Transdermales therapeutisches system für die verabreichung carboxylgruppenhaltiger, nichtsteroidaler antiphlogistika, sowie verfahren zu seiner herstellung | |
DE4241874C2 (de) | Medizinisches Pflaster für die perkutane Verabreichung des Wirkstoffs Ketoprofen | |
EP0617972B1 (de) | Dermales therapeutisches System aus einer schmelzfähigen Poly(meth)-acrylat-Mischung | |
EP0697860B1 (de) | Estradiolhaltiges transdermales therapeutisches system | |
DE69218932T2 (de) | Transdermale therapeutische Formulierung | |
EP0802789B1 (de) | Estradiolhaltiges pflaster | |
DE19728517C2 (de) | TTS zur Verabreichung von Sexualsteroidhormonen und Verfahren zu seiner Herstellung | |
DE69020875T2 (de) | Oestrogenhaltiges Gelpräparat. | |
EP0659081B1 (de) | Dexpanthenol-haltiges pflaster zur transdermalen applikation von steroidhormonen | |
DE19830649A1 (de) | Topisches Pflaster mit nichtsteroidalen Antirheumatika mit Säuregruppe | |
WO2000064418A2 (de) | Transdermales therapeutisches system mit neutralisierten acrylhaftklebern | |
EP0739199A1 (de) | Estradiol-penetrationsverstärker zur transdermalen verabreichung | |
EP1089719B1 (de) | Transdermales therapeutisches system, enthaltend hormone und kristallisationsinhibitoren | |
EP0305726B1 (de) | Transdermales therapeutisches System | |
EP1385490B1 (de) | Haftkleber auf basis von ethylen-vinylacetat-copolymeren und klebharzen, für medizinische verwendungszwecke | |
DE69108512T2 (de) | Estradiol enthaltende transdermale zubereitung. | |
DE10035891A1 (de) | Medizinischer Haftkleber mit einer zweiphasigen Klebermatrix aus Polyacrylaten und Polyaminsalzen | |
DE60013431T2 (de) | Transdermale vorrichtung zur verabreichung von testosteron oder einem derivat davon | |
EP0742716B1 (de) | Pharmazeutische zusammensetzung zur systemischen transdermalen verabreichung mit dem wirkstoff morphin-6-glucuronid | |
DE19828274C2 (de) | Transdermales therapeutisches System, enthaltend Hormone und Kristallisationsinhibitoren | |
DE4438989C2 (de) | Scopolaminpflaster | |
DD279818A1 (de) | Verfahren zur herstellung eines medizinischen pflasters | |
DD281120A5 (de) | Verfahren zur herstellung eines testpflasters | |
DE29923292U1 (de) | TTS zur Verabreichung von Sexualsteroidhormonen |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20030627 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
17Q | First examination report despatched |
Effective date: 20041020 |
|
GRAP | Despatch of communication of intention to grant a patent |
Free format text: ORIGINAL CODE: EPIDOSNIGR1 |
|
GRAS | Grant fee paid |
Free format text: ORIGINAL CODE: EPIDOSNIGR3 |
|
GRAA | (expected) grant |
Free format text: ORIGINAL CODE: 0009210 |
|
AK | Designated contracting states |
Kind code of ref document: B1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: FG4D Free format text: NOT ENGLISH |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: EP |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: FG4D Free format text: LANGUAGE OF EP DOCUMENT: GERMAN |
|
REF | Corresponds to: |
Ref document number: 50212267 Country of ref document: DE Date of ref document: 20080626 Kind code of ref document: P |
|
REG | Reference to a national code |
Ref country code: PT Ref legal event code: SC4A Free format text: AVAILABILITY OF NATIONAL TRANSLATION Effective date: 20080813 |
|
REG | Reference to a national code |
Ref country code: SE Ref legal event code: TRGR |
|
REG | Reference to a national code |
Ref country code: GR Ref legal event code: EP Ref document number: 20080402063 Country of ref document: GR |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FG2A Ref document number: 2307737 Country of ref document: ES Kind code of ref document: T3 |
|
PLBE | No opposition filed within time limit |
Free format text: ORIGINAL CODE: 0009261 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT |
|
26N | No opposition filed |
Effective date: 20090217 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: MC Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES Effective date: 20090131 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R082 Ref document number: 50212267 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 15 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 16 |
|
REG | Reference to a national code |
Ref country code: FR Ref legal event code: PLFP Year of fee payment: 17 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: LU Payment date: 20210120 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: NL Payment date: 20210120 Year of fee payment: 20 Ref country code: PT Payment date: 20210107 Year of fee payment: 20 Ref country code: CH Payment date: 20210120 Year of fee payment: 20 Ref country code: FR Payment date: 20210121 Year of fee payment: 20 Ref country code: FI Payment date: 20210121 Year of fee payment: 20 Ref country code: IE Payment date: 20210121 Year of fee payment: 20 Ref country code: GR Payment date: 20210120 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: DK Payment date: 20210122 Year of fee payment: 20 Ref country code: GB Payment date: 20210121 Year of fee payment: 20 Ref country code: ES Payment date: 20210324 Year of fee payment: 20 Ref country code: DE Payment date: 20210120 Year of fee payment: 20 Ref country code: BE Payment date: 20210120 Year of fee payment: 20 Ref country code: AT Payment date: 20210121 Year of fee payment: 20 Ref country code: SE Payment date: 20210120 Year of fee payment: 20 Ref country code: TR Payment date: 20210115 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: CY Payment date: 20210111 Year of fee payment: 20 |
|
PGFP | Annual fee paid to national office [announced via postgrant information from national office to epo] |
Ref country code: IT Payment date: 20210121 Year of fee payment: 20 |
|
REG | Reference to a national code |
Ref country code: DE Ref legal event code: R071 Ref document number: 50212267 Country of ref document: DE |
|
REG | Reference to a national code |
Ref country code: NL Ref legal event code: MK Effective date: 20220116 |
|
REG | Reference to a national code |
Ref country code: DK Ref legal event code: EUP Expiry date: 20220117 |
|
REG | Reference to a national code |
Ref country code: CH Ref legal event code: PL |
|
REG | Reference to a national code |
Ref country code: GB Ref legal event code: PE20 Expiry date: 20220116 |
|
REG | Reference to a national code |
Ref country code: BE Ref legal event code: MK Effective date: 20220117 |
|
REG | Reference to a national code |
Ref country code: FI Ref legal event code: MAE |
|
REG | Reference to a national code |
Ref country code: IE Ref legal event code: MK9A |
|
REG | Reference to a national code |
Ref country code: AT Ref legal event code: MK07 Ref document number: 395050 Country of ref document: AT Kind code of ref document: T Effective date: 20220117 |
|
REG | Reference to a national code |
Ref country code: ES Ref legal event code: FD2A Effective date: 20220426 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: IE Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20220117 Ref country code: GB Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20220116 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: PT Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20220126 |
|
PG25 | Lapsed in a contracting state [announced via postgrant information from national office to epo] |
Ref country code: ES Free format text: LAPSE BECAUSE OF EXPIRATION OF PROTECTION Effective date: 20220118 |